Obesity Alters the Expression of Suppressive Factors in Intra‐Tumoral Dendritic Cells Following Combinatorial Immunotherapy

Abstract

A growing literature suggests that obesity induces dysregulated antitumor immunity. We found previously that diet‐induced obesity (DIO) increases the abundance of intra‐tumoral regulatory dendritic cells (DCs) in a murine model of renal cancer. Furthermore, DIO reduces the efficacy of an immunotherapy consisting of intra‐tumoral delivery of replication‐deficient adenovirus (Ad) encoding tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) (AdT) plus class B oligonucleotides (CpG1826). This therapy primes endogenous T cells by targeting DCs that process and present tumor‐derived antigens released by TRAIL‐mediated tumor cell death. Our current study evaluated the efficacy of AdT/CpG combined with either anti‐PD‐1 or anti‐CTLA‐4 immune checkpoint blockade, in the absence or presence of DIO. BALB/c mice (7–8‐weekold) were randomized to standard chow or high‐fat diet for 20 weeks prior to the orthotopic injection of Renca‐Luc renal cancer cells into the left kidney and were maintained on diets until day 28 post‐tumor injection. At day seven post‐tumor injection, mice were re‐injected in the left kidney with saline or AdT/CpG. Mice were further randomized to receive intra‐peritoneal isotype control, anti‐PD‐1, or anti‐CTLA‐4. Both AdT/CpG+anti‐PD‐1 (p<0.001) and AdT/CpG+anti‐CTLA‐4 (p<0.001) resulted in a significant reduction in renal tumor outgrowth and spontaneous lung metastasis in lean mice on standard chow. AdT/CpG increased the accumulation of intra‐tumoral DCs independent of dietary or immunotherapy intervention, with the conventional DC two (cDC2) subset favored over the conventional DC one (cDC1) subset. Expression of PD‐1 and PD‐L1 on DC subsets was unchanged in response to diet or immunotherapy intervention; however, untreated tumor‐bearing DIO mice had elevated PD‐1 expression on cDC1s (p=0.022) compared to untreated lean mice or lean mice receiving AdT/CpG+anti‐PD‐1. Lastly, Arginase‐1 expression in cDC1s was not significantly different between groups; however, Arginase‐1 expression was elevated in response to DIO on cDC2s (p=0.006) compared to both lean and DIO AdT/CpG+anti‐PD‐1 treated mice. Future studies are needed to characterize the suppressive function of intra‐tumoral DC populations, as well as the T cell priming capacity of DCs within tumor‐draining lymph nodes in response to immunotherapy in the absence or presence of DIO. In conclusion, the differential response to immunotherapy and alteration in suppressive factors in intra‐tumoral DCs in DIO mice warrants further investigation, as targeting these pathways may ultimately enhance treatment strategies in overweight and obese cancer patients.Support or Funding InformationRO1CA181088 and T32DK062710This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.